Daniel Su, MD: Value of Oral APX3330 for Diabetic Retinopathy Progression

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Daniel Su, MD describes the promise of APX3330 for delaying or preventing diabetic retinopathy progression in a post-hoc analysis of the ZETA-1 trial.

Oral APX3330, a Ref-1 inhibitor, demonstrated a clinically meaningful reduction in the progression of diabetic retinopathy on a binocular 17-step Diabetic Retinopathy Severity Scale (DRSS) person-level scale, according to new data presented at the Association for Research in Vision and Ophthalmology (ARVO) 2024 Meeting.

A posthoc analysis of the phase 2 ZETA-1 trial, data showed a reduction in binocular ≥3-step and ≥4-step worsening in APX3330 treated subjects compared with placebo, supporting its role as a promising oral agent for delaying the progression of non-proliferative DR (NPDR) to proliferative DR (PDR).

In an interview with HCPLive, Daniel Su, MD, Retina Vitreous Associates Medical Group, noted the significant disease burden of DR highlights the need for less burdensome, non-invasive therapies to prevent the progression to more severe disease stages.

“The idea of an oral agent is very attractive. It’s something patients can continue to be on treatment, even though they may not return for an in-office injection,” Su told HCPLive. “You have something that can stabilize the disease, or even protect against progression, and it will be very valuable because you potentially avoid some vision-threatening complications down the line.”

ZETA-1 was a multi-center, randomized, placebo-controlled, double-masked, phase 2 clinical trial that included 103 participants with DRSS scores of 47, 53, or 61 without center-involved DME (CI-DME) in the study eye. These patients were randomized 1:1 to receive 600 mg APX3330 or placebo.

ZETA-1 did not meet its primary endpoint of the percentage of patients with a ≥2-step improvement in DRSS at week 24 in the study eye. Given its oral delivery, Ocuphire Pharma indicated the importance of measuring the effect of APX3330 on both eyes.

A posthoc analysis was performed in participants without CI-DME and DRSS scores of 43, 47, and 53 in both eyes using a binocular 17-step DRSS person-level scale—this was a US Food and Drug Administration (FDA) confirmed scale for evaluation of systemic agents in diabetic retinopathy. This was determined based on an end-of-phase 2 meeting with the FDA and the inclusion criteria and scale used in the posthoc analysis will further APX3330 studies into phase 3.

Upon analysis, 68 participants with 2 qualified eyes displayed a numerical reduction from baseline in binocular ≥3-step worsening on a DRSS person-level scale at week 24. More patients (15.2%) treated with placebo experienced worsening compared with patients (5.7%) treated with APX3330 (P = .26).

In addition, the analysis showed a numerical reduction of binocular ≥4-step worsening, with 15.2% of placebo-treated patients, compared with 0% of APX3330 subjects (P = .07). Altogether, this represented a 61% reduction in binocular ≥3-step worsening and a 100% reduction in ≥4-step worsening between the placebo and APX3330-treated groups.

Moreover, participants in the APX3330 group developed PDR by week 24 compared to the placebo group (11% vs 26% respectively; p=0.13). Based on these phase 2 data, further evaluation of APX3330 in upcoming phase 2/3 trials may warranted to define the oral drug’s capabilities for DR.

“If we can get these patients stable and prevent progression to PDR with oral therapy, that would be a significant development in the treatment of diabetic retinopathy arena,” Su told HCPLive. “And I think this post hoc analysis supports further evaluation of this oral agent in upcoming trials.”

Disclosures: Relevant disclosures for Su include consultant and contractor roles with Ocuphire Pharma and Regeneron.


Su D, Pepose JS, Withers B, Brigell MG, Lazar A, Patel R, Magrath G, Kaiser PK, Boyer DS. Oral APX3330, a Ref-1 Inhibitor, Slows Progression of Diabetic Retinopathy on a Binocular DRSS Person-Level Scale. Paper presented at the Association for Research in Vision and Ophthalmology (ARVO) 2024 Meeting, May 5–9, 2024.

Iapoce C. Oral APX3330 receives FDA Nod for Phase 3 endpoint in Diabetic Retinopathy. HCP Live. December 1, 2023. Accessed May 7, 2024.